TY - JOUR
T1 - ASR490, a small molecule, overrides aberrant expression of notch1 in colorectal cancer
AU - Tyagi, Ashish
AU - Chandrasekaran, Balaji
AU - Kolluru, Venkatesh
AU - Baby, Becca V.
AU - Sripathi, Cibi A.
AU - Ankem, Murali K.
AU - Ramisetti, Srinivasa R.
AU - Chirasani, Venkat R.
AU - Dokholyan, Nikolay V.
AU - Sharma, Arun K.
AU - Damodaran, Chendil
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Notch1 activation triggers significant oncogenic signaling that manifests as enhanced metastatic potential and tumorigenesis in colorectal cancer. Novel small-molecule inhibitors, mainly plant-derived analogs, have low toxicity profiles and higher bioavailability. In this study, we have developed a small molecule, ASR490, by modifying structure of naturally occurring compound Withaferin A. ASR490 showed a growth-inhibitory potential by downregulating Notch1 signaling in HCT116 and SW620 cell lines. Docking studies and thermal shift assays confirmed that ASR490 binds to Notch1, whereas no changes in Notch2 and Notch3 expression were seen in colorectal cancer cells. Notch1 governs epithelial-to-mesenchymal transition signaling and is responsible for metastasis, which was abolished by ASR490 treatment. To further confirm the therapeutic potential of ASR490, we stably overexpressed Notch1 in HCT-116 cells and determined its inhibitory potential in transfected colorectal cancer (Notch1/HCT116) cells. ASR490 effectively prevented cell growth in both the vector (P ¼ 0.005) and Notch1 (P ¼ 0.05) transfectants. The downregulation of Notch1 signaling was evident, which corresponded with downregulation of mesenchymal markers, including N-cadherin and b-catenin and induction of E-cadherin in HCT-116 transfectants. Intraperitoneal administration of a 1% MTD dose of ASR490 (5 mg/kg) effectively suppressed the tumor growth in control (pCMV/HCT116) and Notch1/HCT116 in xenotransplanted mice. In addition, downregulation of Notch1 and survival signaling in ASR-treated tumors confirmed the in vitro results. In conclusion, ASR490 appears to be a potent agent that can inhibit Notch1 signaling in colorectal cancer.
AB - Notch1 activation triggers significant oncogenic signaling that manifests as enhanced metastatic potential and tumorigenesis in colorectal cancer. Novel small-molecule inhibitors, mainly plant-derived analogs, have low toxicity profiles and higher bioavailability. In this study, we have developed a small molecule, ASR490, by modifying structure of naturally occurring compound Withaferin A. ASR490 showed a growth-inhibitory potential by downregulating Notch1 signaling in HCT116 and SW620 cell lines. Docking studies and thermal shift assays confirmed that ASR490 binds to Notch1, whereas no changes in Notch2 and Notch3 expression were seen in colorectal cancer cells. Notch1 governs epithelial-to-mesenchymal transition signaling and is responsible for metastasis, which was abolished by ASR490 treatment. To further confirm the therapeutic potential of ASR490, we stably overexpressed Notch1 in HCT-116 cells and determined its inhibitory potential in transfected colorectal cancer (Notch1/HCT116) cells. ASR490 effectively prevented cell growth in both the vector (P ¼ 0.005) and Notch1 (P ¼ 0.05) transfectants. The downregulation of Notch1 signaling was evident, which corresponded with downregulation of mesenchymal markers, including N-cadherin and b-catenin and induction of E-cadherin in HCT-116 transfectants. Intraperitoneal administration of a 1% MTD dose of ASR490 (5 mg/kg) effectively suppressed the tumor growth in control (pCMV/HCT116) and Notch1/HCT116 in xenotransplanted mice. In addition, downregulation of Notch1 and survival signaling in ASR-treated tumors confirmed the in vitro results. In conclusion, ASR490 appears to be a potent agent that can inhibit Notch1 signaling in colorectal cancer.
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U2 - 10.1158/1535-7163.MCT-19-0949
DO - 10.1158/1535-7163.MCT-19-0949
M3 - Article
C2 - 33087513
AN - SCOPUS:85100491728
SN - 1535-7163
VL - 19
SP - 2422
EP - 2431
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 12
ER -